Outline

• Metabolic fate of fatty acids during fasting

• Ketogenesis and ketolysis
• Ketogenesis in disease condition
• De novo synthesis of fatty acids
– Synthesis of palmitate and regulation
– Synthesis of Triacylglycerol and VLDL
• Elongation and desaturation of fatty acids
• Ecosanoids: Synthesis, physiological role, and some clinical and
therapeutic aspects
• Metabolism of glycerophospholipids and sphingolipids
• Metabolism of cholesterol, bile salt synthesis and gall stones
1
Fate of Fatty Acid During fasting

Triacylglycerol lipolysis in
adipose
↓
 Fatty acid release to blood
↓
 May results in
 Complete oxidation (in
extrahepatic tissues)
 Ketone bodies (Most
liver fatty acid)
2
KETONE BODIES

Formation
&
Oxidation
3
Ketone bodies: Formation, utilization, and excretion
during fasting state

4
Ketone body
synthesis

5
Key Steps for Regulation of Ketogenesis

CPT I: Carnitine
palmitoyl transferase I
(Carnitine:acyl
carnitine translocase I/
CAT-1)

6
 Regulation of ketone body synthesis
 Mainly by Insulin/Glucagon  Ketogenesis during fasting
 Insulin promotes fatty acid synthesis by
increasing Acetyl-CoA carboxylase activity.
 Malonyl CoA inhibit Carnitine palmitoyl
transferase I (CPT I)

 Glucagon increases lipolysis.

 Oxidation supplies NADH and FAD(2H), ATP
synthesis
 As ATP levels increase, less NADH is
oxidized, and high NADH/NAD
 Oxaloacetate is converted into malate
because of high NADH levels, and malate
enters the cytoplasm for gluconeogenesis.
 Acetyl-CoA is diverted from the TCA cycle
into ketogenesis, in part because of low
7
oxaloacetate levels
Oxidation of ketone bodies
 Liver lacks thiophorase (β-ketoacyl-
CoA transferase, also called succinyl
CoA:Acetoacetate CoA transferase/
succinyl-CoA:3-ketoacid-CoA
transferase, SCOT ), is ‘altruistic organ’,
 Energy yield from ketone bodies
 From 2Acetyl CoA (additionally from1
NADH if β-Hydroxybutyrate used)

 Utilization of ketone bodies

 All tissues especially during fasting (eg.
Fetus, brain) except RBC & liver
 Adipose tissue and intestinal mucosa
during fasting more than fatty acid
 Fatty acid is mainly preferred by skeletal 8
muscles, heart, liver.
 Ketogenesis in disease condition
 Ketone Bodies in Type 1 Diabetes
 1. FFA and KB are increased, ketogenesis is activated to
provide substituted energy source.
 2. Delivery of FFA substrate to the liver is not blocked
(absence of the blocking effect of insulin )
 3. An unrestricted KB accumulation leads to metabolic
acidosis (Diabetic Keto-acidosis)
 Ketosis: 90 mg/100 mL (compared with a normal level of 3
mg/100 mL) and urinary excretion of 5,000 mg/24 hr
(compared with a normal rate of 125 mg/ 24 hr).

9
 Ketogenesis in disease condition

 Ketone Bodies in Type 2 Diabetes

 FFA usually elevated
 Mild elevation of ketone bodies (not like type I DM)
 Ketone Bodies in Hyperthyroidism
 Increased lipolysis (more FFA) = increased substrate
delivery
 Increased lipid oxidation
 All levels of FFA, Glycerol and KB are elevated .

10
 FATTY ACID SYNTHESIS
• Carbon source
• Dietary carbohydrate (major)  Acetyl CoA
• Excess dietary protein  Acetyl CoA/ TCA intermediate

• Types of fatty acids synthesized: Saturated & unsaturated

• Organ– Mainly liver (cytosol) & some in adipose, lactating mammary gland,
renal cortex and brain cells

• Synthesis: can be categorized in to 4 stages (e.g. Palmitic acid)

• Acetyl CoA formation transfer from mitochondria to cytosol

• Generation of cytosolic acetyl CoA

• Formation of malonyl CoA from acetyl CoA

• Assembly of fatty acid chain by fatty acid synthase

• Thiolysis: release of fatty acid from Acyl Carrier Protein

11
Provision of acetyl-CoA & NADPH for lipogenesis

Acetyl-CoA NADPH

12
 Sources and Fates of Acetyl CoA
Sources of active acetate
- Pyruvate (from glucose)
- Oxidation of ethanol,
- Oxidation of fatty acids
- Ketolysis
- Amino acids

13
Carboxylation of Acetate

14
 Synthesis (cont.)
• Synthesis of palmitate in cytosol

• Synthesis on fatty acid synthase

• FA synthase has Two identical dimers - head-to-tail associated

– Each have 3 domains (condensation, reduction and releasing
units) with 7 catalytic activity & ACP segment

– ACP segment contain phosphopantetheine residue

– Phosphopantetheinyl sulfhydryl group on one subunit and a

cysteinyl sulfhydryl group on another subunit

• Further elongation in ER
15
Fatty acid synthase

Reduction unit
Condensing unit

A site Releasing unit

B site

16
 Fatty acid synthesis on Fatty acid synthase (simplified
form)
Steps of Biosynthesis
a`. Precursors loading
b. Condensation
c. Reductions
d. Traslocation
e. Cycling:
f. Thiolysis
ii.Types of Thiolases
- Low carbon atom fatty acids
(  10 C)
- Intermediate chain (C12 &
C14)
- Specific for C16 17
 Steps of fatty acid synthesis on Fatty acid synthase

Mammary gland has thioesterases that can releases the synthesized 4, 6, 8, 10, 12 or
14 carbons 18
Summary of fatty
acid synthesis

19
 Regulation of FA synthesis
Rapid short term regulation
Insulin
- Enhance uptake of glucose by adipocytes
- Increase PDH activity
- Decrease cAMP by activating phosphatase
Glucagon - Increase cAMP
- deactivate ACoA carboxylase
- activates phosphoprotein phosphatase inhibitor-1

Slow long term regulation – Enzyme synthesis

Inducers- High-carbohydrate diet or a fat-free diet and insulin
Reppressors - high-fat diet (long-term effect), fasting, glucagon level &
diabetes mellitus 20
 Regulation of FA synthesis

 Rate limiting enzyme for fatty acid

synthesis - acetyl CoA
carboxylase
 Type of Regulation
 At the level of Enzyme synthesis
 At the steady state level*
 Allosteric regulation
 activation by Citrate
 inhibition by Palmitoyl CoA
 Hormonal regulation/ Covalent
modification
 activation by dephosphorylation
 active form polymerizes into a
filament
 Phosphorylated form depolymerizes
21
 Mainly microsomes of the
liver, kidneys, mammary
glands, adrenal glands,
adipose tissue and intestinal
mucosa

 All other tissues synthesize

in small amount.

 Glycerol kinase found in

liver, kidney, intestine

22
The fate of TG synthesized in Liver: VLDL synthesis

23
 Fatty Liver (hepatic steatosis)

 Definition: Chronic accumulation of lipid in liver leads to

fibrotic changes in the cells that progress to cirrhosis and impaired
liver function.

 Causes: mainly two causes

 1) Raised level of plasma free fatty acids:
 caused by adipose tissue lipolysis or increased LPL by
extrahepatic tissues.
 occurs during starvation, high-fat diets, uncontrolled
diabetes mellitus
 2) Metabolic block in the production of plasma lipoproteins
Additional causes: E.g. Ethanol 24
 Microsomal Fatty Acid Elongation
 The most active system
 2C addition from malonyl CoA but no ACP
 2C addition to palmitoyl-CoA / C10 - C18 unsaturated fatty acyl-
CoAs
 Very long chain (C22-C24) also produced particularly in brain
 Important for elongation of dietary linoleic acid & α-linolenic acid
into arachidonic acid & eicosapentaenoic acid (neuron fat)
respectively by desaturation.
 Arachidonate and eicosapentaenoate are essential for eicosanoid and
sphingolipid synthesis
 Dietary defficiency results in poor growth, wound healing and
dermatitis 25
Microsomal elongase system
(from C10 upward)

 Although NADH is used, NADPH is

preferred.

26
 Mitochondrial chain elongation

Mitochondrial structural lipids

Stimulated during anaerobic &

high NADH.H+/NAD ratio

Uses acetyl-CoA & NADH

27
 Desaturation of Fatty Acids
• Requirement
• O2, NADH, and cytochrome b5, non-heme iron containing mixed-
function oxygenases.
• Intracellular Site – Endoplasmic reticulum
• Reaction
Oxidation of both the Fatty acid & NADH
Common desaturation at C9, but also at C4, C5 & C6
 Linoleic acid (6 FA)  Elongation & Desaturation
↓
Prostaglandins & other Eicosanoids  Arachidonic
acid
 -linolenic acid (3 FA)  Elongation & Desaturation
↓
Eicosanoids precursor  Eicosapentaenoic acid
28
 Unsaturated FAs
 Linoleic (ω6) or α-linolenic (ω3)
acids required for the synthesis of the
other members of the ω6 or ω3
families must be supplied in the diet.
 Required in the diet for at least two
reasons:
 It serves as a precursor of
arachidonic acid from which
eicosanoids are produced.
 It covalently binds another
fatty acid attached to
cerebrosides in the skin, forming
an unusual lipid
(acylglucosylceramide) that
helps to make the skin
impermeable to water.
 Deficiency leads to red, scaly
dermatitis and other skin problems
29
 Desaturation of fatty acids

 Fatty acid desaturase is a mixed function oxidase.

 It oxidizes two substates (fatty acid and
30
NADPH/NADH)simultaneously
 Other Fatty Acid Derivatives
• Other fatty acids are derived from
Palmitate
• Each step is catalyzed by the microsomal
chain elongation or desaturase system:
• Because mammals do not have the
desaturases necessary to produce
linoleate and -linolenate, these are
essential fatty acids, must be present in
diet
• Desaturation and chain elongation system
is greatly diminished during
– fasting state
– upon glucagon and epinephrine
administration
– in the absence of insulin as in type I diabetes
mellitus. 31
 Other Fatty Acid Derivatives

• Docosahexaenoic acid (DHA; 3, 22:6) which is synthesized from a-linolenic

acid or obtained directly from fish oils, is present in high concentrations in
retina, cerebral cortex, testis, and sperm.
• DHA is needed for development of the brain and retina and is supplied via the
placenta and milk.
• Premature infants have a low ∆4 desaturase ability, reducing their potential for
synthesizing DHA from -3 fatty acids precursors.
• In essential fatty acid deficiency, nonessential polyenoic acids of the 9 family
replace the essential fatty acids in phospholipids, particularly with ∆5,8,11-
eicosatrienoic acid.
• The triene:tetraene ratio in plasma lipids can be used to diagnose the extent of
essential fatty acid deficiency.
• These fatty acids are found in high concentrations in vegetable oils.
32
 Deficiency symptoms in the absence of
essential fatty acids from the diet

 Non-lipid diet plus vitamins A and D

 Reduced growth rate and reproductive deficiency
• Deficiency syndrome was cured by the addition of linoleic, -
linolenic, and arachidonic acids to the diet.
• Essential fatty acids are found in structural lipids of the cell
and are concerned with structural integrity of mitochondrial
membrane.
• Arachidonic acid is present in membranes and accounts for 5-
15% of the fatty acids in phospholipids.

33
Trans-fatty acids compete with cis-fatty acids
 Large amounts of trans-unsaturated fatty acids in partially
hydrogenated vegetable oils (e.g., margarine) raises the
question of their safety as food additives.
• They are metabolized more like saturated than like the cis-
unsaturated fatty acids.
• Trans-polyunsaturated fatty acids do not possess essential
fatty acid activity and may antagonize the metabolism of
essential fatty acids and enhance essential fatty acid
deficiency.
• Trans-fatty acids raise plasma LDL levels and lower HDL
levels.

34
Comparison of fatty acid oxidation and fatty acid synthetic pathways

-Oxidation Fatty acid synthesis

Site Mitochondria. Cytosol.

Enzyme Four separate enzymes. A dimeric multifunctional enzyme
system complex.
Intermediates CoA derivatives. The enzyme-bound growing fatty
acid.
Carbon units One acetyl-CoA released One initial acetyl-CoA primer is
each cycle. followed by one malonyl-CoA
adding 2C each cycle.
Coenzymes NAD+/FAD+ generate NADPH is consumed into NADP.
NADH/FADH2.
Regulated by Energy level and Malonyl- Citrate at the level of malonyl-CoA
CoA. synthesis. 35
Eicosanoids and their biosynthetic origins

36
 EICOSANOIDS - General
 Paracrine and autocoids with potent effects on virtually every
tissue in the body.

 Derived from metabolism of 20-carbon (arachidonate is common),

unsaturated fatty acids synthesized throughout the body
(eicosanoic acids).
 Give rise to eicosanoids; PG, TX, LT, and lipoxins (LX/LP).

• Eicosanoids are pharmacologically and physiologically active

compounds.

• Act as hormones functioning through G-protein linked receptors.

• The eicosanoids all have short plasma half-lives (typically 0.5—5

min).
37
Eicosanoid Synthesis- General

38
 EICOSANOIDS - General
 Synthesis can be very tissue specific:

 PGI2: endothelial and vascular smooth muscle cells.

 Tromoxane (TX) synthesis: primarily in platelets.

 Hydroperoxyeicosatetraenoic acids (HpETEs),

hydroxyeicosatetraenoic acids (HETEs), and the LT:
predominantly in mast cells, WBCs, airway epithelium, and
platelets.

 Most catabolism occurs in the lung and excreted in the urine.

 TXA2 is rapidly hydrated to the less active TXB2.

 PGI2 is hydrolyzed to 6-keto-PGF1α.

39
 CYCLOOXYGENASE pathway
• Prostaglandin H2 synthase (PGHS) and two molecules of oxygen.
• PGH2 is a precursor for other prostaglandins and thromboxanes
• There are two PGHS isoenzymes, PGHS-1 (COX-1) and PGHS-2
(COX-2). Each isoenzyme has cyclooxygenase and peroxidase
activities.
• Role of COX-1 include COX-1 gastric mucin secretion, regulation of
vascular homeostasis, and renal blood flow. COX-2 mediate
inflammation, pain, and fever.
• Each cell type produces only one type of prostanoid.
• Termination of prostaglandin formation is partly by self-catalyzed
destruction ("suicide enzyme.“)
• Aspirin, a nonsteroidal anti-inflammatory drug (NSAID), inhibits both
Cox-1 and 2 by acetylation.
• Other NSAIDs, such as ibuprofen, inhibit cyclooxygenases as a
reversible competitive inhibitor.
40
Cyclooxygenase pathway

41
 Lipooxygenase pathway
• Produce leukotrienes
from eicosanoic acids
in leukocytes,
platelets, and
macrophages in
response to both
immunologic and
non-immunologic
stimuli.
• Lipoxygenases add
both oxygen atoms
to arachidonate to
synthesize
leukotrienes
42
 Lipoxins
• The lipoxins are derived
from AA and are potent
anti-inflammatory
molecules.
• Lipoxin synthesis requires
coordinated activity of
neutrophil 5-lipoxygenase
and a related enzyme
(either 12-lipoxygenase or
15-lipoxygenase) from
another cell type—either
platelets or endothelial cells
• Lipoxins are endogenous
anti-inflammatory pro-
resolving molecules. 43
 Biological Action
• Vascular smooth muscle
• PGE2 and PGI2 are potent vasodilators in most vascular beds.
• Thromboxane is a potent vasoconstrictor.
• Leukotrienes are vasoconstrictors, increase vascular permeability

• Inflammation
• PGE2 and PGI2 cause an increase in blood flow and promote, but do not
cause, edema.
• Hydroxyeicosatetraenoic acids (HETEs) and LTs cause chemotaxis of
neutrophils and eosinophils.

• Bronchial smooth muscle

• PGFs cause smooth muscle contraction.
• PGEs cause smooth muscle relaxation.
• LTs and TX are potent bronchoconstrictors and are the most likely
candidates for mediating allergic bronchospasm.
44
 Biological Action
– Uterine smooth muscle.
 PGE2 and PGF2a cause contraction of uterine smooth muscle in
pregnant women.
 More variable response to prostaglandins in non-pregnant women
 PGF2a causes contraction
 PGE2 causes relaxation

– Gastrointestinal tract
• PGE2 and PGF2a increase the rate of longitudinal contraction in the
gut and decrease transit time.
• The leukotrienes are GI smooth muscle constriction and mucus
secretion.
• PGE2 and PGI2 inhibit acid and pepsinogen secretion in the
stomach.
• Prostaglandins increase mucus, water, and electrolyte secretion in
the stomach and the intestine. 45
 Biological Action

 Blood
– TXA2 is a potent inducer of platelet aggregation.
– PGI2 and PGE2 inhibit platelet aggregation.
– PGEs induce erythropoiesis by stimulating the
renal release of erythropoietin.
– 5-HPETE stimulates release of histamine
– PGI2 and PGD inhibit histamine release.

46
 Therapeutic uses
Induction of labor at term
 Induction of labor is produced by:
 Infusion of PGF2a (carboprost tromethamine) [Hemabate] or PGE2
(dinoprostone) [Prostin E].

 Therapeutic abortion:
A. Inducing abortion in the second trimester
B. Inducing first-trimester abortion
Treatment of peptic ulcer: Misoprostol [Cytotec], a methylated
derivative of PGE1
 is approved for use in patients taking high doses of nonsteroidal
antiinflammatory drugs (NSAIDs) to reduce gastric ulceration.
 Erectile dysfunction:
 Alprostadil (PGE1) can be injected directly into the corpus cavernosum or
administered as a transurethral suppository to cause vasodilation.
47
 METABOLISM OF
GLYCEROPHOSPHOLIPIDS
AND
SPHINGOLIPIDS

48
Biosynthesis of Acylglycerols -Overview

49
Overview of Acylglycerol Biosynthesis

50
 Glycerophospholipids

• Source: Fatty acids: dietary or denovo

synthesis

• Function:

– Components of blood lipoproteins, bile & lung

surfactant

• Premature infant has not yet begun to produce

adequate amounts of lung surfactant.

– Sources of PUFAs, particularly arachidonic acid

(ecosanoid precursor) 51
 Synthesis of glycerophospholipids
 Phosphatidic acid synthesis is similar to triacylglycerol

 Two mechanisms of glycerophospholipid synthesis

 Activation of head group

 Activation of diacylglycerol

CTP: Cytidine triphosphate

52
 Summary: Synthesis of phosphatidylcholine,
phosphatidylethanolamine, and phosphatidylserine

SAM: S-adenosyl methionine

 Dietary choline is necessary since denovo synthesis from glucose is 53

inadequate.
 Summary: Synthesis of
Phosphatidylglycerol, Cardiolipin &
Phosphatidylinositol

54
 Degradation of Glycerophospholipids
• By Phospholipases located in cell
membranes or in lysosomes
• C2 contain usually unsaturated, frequently
arachidonic acid and removed usually in
response to signals for eicosanoids
biosynthesis
• PLC hydrolyzes PIP2 to produce DAG and
IP3
• PLA2 provides the major repair mechanism
for membrane lipids damaged by oxidative
free radical reactions.

55
Ether Glycerolipids Summary of ether lipids biosynthesis

- Long-chain fatty alcohol forms an ether

linkage with C1
- Plasmalogen
1-Acyldihydroxyacetone
- Ethanolamine plasmalogen is found phosphate
in myelin
- Choline plasmalogen found in heart 1-Alkyldihydroxyacetone
phosphate
muscle
- Platelet activating factor (PAF)
- Acetyl group replaces fatty acyl at C2 1-Alkyl-2-acylglycerol-
and alkyl group at C1 is saturated 3-phosphate

- Synthesized in peroxisomes
- PAF is released from phagocytic
blood cells in response to various
stimuli.
- It causes platelet aggregation,
edema and it is involved in the allergic
56
response.
 Sphingolipids
• Source: dietary or de novo synthesis
• Function:
– Serve in intracellular communication (signaling) including
apoptosis and cell senescence,
– differentiation, and opposes some of the actions of
diacylglycerol.
– myelin sheath (nerve conduction)
– As antigenic determinants of ABO blood group

• Synthesis
– Degradation is by lysosomal enzymes 57
Biosynthesis of ceramide

58
 Synthesis of sphingolipids from ceramide
– Addition of phosphocoline OR carbohydrates to ceramide

PAPS ( Active sulfate donor)

59
 CLINICAL ASPECTS
• Deficiency of Lung Surfactant Causes Respiratory Distress
Syndrome
• Lung surfactantis composed mainly of lipid with some
proteins and carbohydrate and prevents the alveoli from
collapsing.
• Surfactant activity is largely attributed to
dipalmitoylphosphatidylcholine, which is synthesized shortly
before parturition in full-term infants.
• Deficiency of lung surfactant in the lungs of many preterm
newborns gives rise to respiratory distress syndrome.
• Administration of either natural or artificial surfactant has
been of therapeutic benefit.
60
 Sphingolipidoses (lipid storage diseases)
• Group of inherited diseases that are often manifested in
childhood.
• These diseases are part of a larger group of lysosomal disorders
and exhibit several constant features:

– Cellular accumulation of ceramide-containing lipids

particularly in neurons, causing neurodegeneration.

• The rate of synthesis of the stored lipid is normal.

– Defect is in the lysosomal degradation pathway of

sphingolipids.

– The extent to which the activity of the affected enzyme is

decreased is similar in all tissues. 61
Metabolism
of
Cholesterol

62
 CHOLESTEROL SYNTHESIS, TRANSPORT, AND
EXCRETION
• Present in tissues and in plasma lipoproteins as free cholesterol or as cholesteryl ester (two-
third).

• Synthesized in many tissues mainly by liver to distribute as VLDL, although the gut, the
adrenal cortex, the gonads as well as the placenta in pregnant women produce significant
quantities of the sterol.

• It is the precursor of all other steroids, such as sex hormones, bile acids, and vitamin D.

• It occurs in foods of animal origin such as egg yolk, meat, liver, and brain.

• A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), and
the remainder is provided by the average diet.

• The liver accounts for 10% of total synthesis in humans, the intestine for about another
10%.

• Synthesis' involves microsomal (ER) and cytosolic fraction

• Free cholesterol also enters the gut lumen via the biliary tract (approximately 1,000 mg /day,
which mixes with 300 mg of dietary cholesterol to form an intestinal pool, roughly 55% of
which is resorbed by the enterocytes and enters the bloodstream daily).
63
• Eliminated in the bile as cholesterol or bile salts.
 Processes that determine the cholesterol balance
● Intestinal uptake of dietary cholesterol
● de novo cholesterol synthesis
● Synthesis of steroid hormones from cholesterol
● Synthesis of bile acids from cholesterol, and their biliary secretion
● Biliary secretion of surplus cholesterol in unmodified form.

 Major steps of biosynthesis

• Formation of mevalonate from acetyl-CoA

• Conversion of Mevalonate to two activated Isoprenes

• Squalene synthesis: Condensation of Six activated 5-Carbon Isoprenes

• Cyclization of squalene to form lanosterol

• Cholesterol synthesis: Lanosterol to cholesterol

64
 Formation of mevalonate
from acetyl-CoA

HMG-CoA reductase, an enzyme

embedded in ER membrane
65
Conversion of
Mevalonate
to
two Activated Isoprenes

66
Condensation of 6 activated 5C
Isoprenes to form the 30-
CSqualene

- Head-to-tail condensation of
isopentenylpyrophosphate and
dimethylallyl pyrophosphate

- Head-to-tail condensation of Geranyl

pyrophosphate with isopentenyl
pyrophosphate

- Head-to-head fusion of two farnesyl

pyrophosphate

67
Cyclization of squalene form lanosterol

Conversion of lanosterol to cholesterol

68
 Metabolic Fates of Cholesterol

 Most part of cholesterol in circulating plasma lipoproteins is esterified form.

69
 Regulation of Cholesterol Biosynthesis
Key regulatory enzyme: HMG-CoA reductase
• Proteolytic degradation
• Transcriptional control
• By covalent modification

A. Regulation by Proteolytic degradation

 HMG-CoA reductase has a sterol-

sensing domain (SSD)

 Increase in cellular sterols (primarily

cholesterol and bile acids), prevent
oligomerization of the enzyme and
activate multiple ubiquitination for
70
degradation within proteosome.
 B. Transcriptional regulation of HMG-CoA reductase (key
regulatory enzyme)

 The gene is controlled by SREBPs (sterol regulatory element-binding

proteins)

 SREBP & SCAP (SREBP cleavage activating protein) exist as a

complex on SER.

 During high cholesterol, SREBPs are inactive complexes with SCAP

(SREBP cleavage- acivating protein) remains on SER.

 Only soluble amino terminal domain of SREBP functions as

transcription activator

 SCAP acts as sterol sensor (by binding to sterols)

71
B. Transcriptional regulation of HMG-CoA reductase (key
regulatory enzyme)
SREBP
activation

72
 C. Hormonal regulation
Glucagon
 Activators: Insulin
+
+
 Dephosphorylate cAMP- Adeny late Cyclase
the enzyme phosphodiesterase
AMP cAMP ATP

 Insulin +
Phosphatase Inhibitor-1
 thyroid Reductase
hormone ATP
Kinase
Pi
- -
Reductase (inactive)
+2
Kinase Kinase Mg Phosphatase
 Inhibitors: ADP
+
Insulin
Reductase H2O
Kinase
 Phosphorylate the HMG-CoA Reductase
(active) HMG-CoA Reductase
(active) (inactive)
enzyme Mg+2
ATP ADP
 Glucagon
- Phosphatase
 Glucocorticoids Cholesterol H2O
and its
derivatives Pi +
Insulin
73
 Dietary and life style factors for Serum Cholesterol Level

• Serum Cholesterol level Increasing Factors

• High saturated fat and high carbohydrate diet

• Low fiber diet

• High chromium and magnesium diet

• Serum Cholesterol level Decreasing Factors

• Exercise, nicotinic acid

• Diet rich in cholesterol and its derivatives, plant sterols,

PUFAs

• Starvation

• Hypolipidemic drugs such as lovastatin & clofibrate. 74

Metabolic Fates of Cholesterol

75
 BILE ACID – A C-24 steroid from Cholesterol

 Derived from cholesterol by hydroxylation, oxidative side-chain shortening to generate a

carboxyl group at C-24, saturation of the 5 double bond of cholesterol and further various
hydroxylation of the steroid nucleus.

Types

 Primary bile acids: synthesized in the liver from cholesterol.

• Mainly 2 types

• Cholic acid (31% of bile acids) & Chenodeoxy cholic acid (45% of bile acids)

• Conjugated with either glycine or taurine (cysteine derivative) in the liver

 Secondary bile acids: by intestinal bacteria from 1o bile acid.

• Deconjugated and dehydroxylated (mainly at C-7) after digestive role is over (become
less soluble).

• Mainly 2 types: Deoxycholic acid (from cholic acid) & Lithocholic acid (from
chenodeoxycholic cholic acid)

• Exist as salt ( with Na & K) - usually as Na-glycocholate & Na-taurocholate

76
 Overview of bile salt metabolism

 Most of the gut bile acids (95%) recycle through the enterohepatic
circulation into the liver through the portal vein bound to serum
albumin to be reconjugated (but not rehydroxylated) and then
resecreted, and, so on. 77
 Rate limiting

BILE ACID SYNTHESIS

78
 Functions Bile Acids

 Emulsifying function of bile helps digesting and absorbing

digested lipids and fat-soluble vitamins.

 Stimulation of the intestinal motility, being choleretic (i.e.,

stimulates its own secretion)

 Solubilization of cholesterol for excretion (with the help of

bile phospholipids),

 Excretion of several toxins, e.g., excess copper

 Buffering the stomach acid.

79
Gall Stones: Cholelithiasis (bile gallbladder
stones)

 It occurs when relative reduction in the amount of the

cholesterol-solubilizing bile acids and/or phospholipids (chiefly
phosphatidylcholine) vs. cholesterol as main components of bile.

 Leads to precipitation of the cholesterol in the bladder and/or

the main bile duct around a core of protein and bilirubin.

 Inflammation and/or infections of the gallbladder could provide

a nucleus upon which such stones could be formed.

 Infants with cholestasis often present with haemorrhagic

complications due to vitamin K deficiency. 80